Small Cause, Great Impact: Modification of the Guanidine Group in the RGD Motif Controls Integrin Subtype Selectivity.

Due to its unique role as a hydrogen-bond donor and its positive charge, the guanidine group is an important pharmacophoric group and often used in synthetic ligands. The chemical modification of the guanidine group is often considered to destroy its function. Herein, we show that the N-methylation, N-alkylation, or N-acylation of the guanidine group can be used to modify the receptor subtype specificity of the integrin ligand cilengitide.

Stable Peptides Instead of Stapled Peptides: Highly Potent αvβ6-Selective Integrin Ligands.

The αvβ6 integrin binds the RGD-containing peptide of the foot and mouth disease virus with high selectivity. In this study, the long binding helix of this ligand was downsized to an enzymatically stable cyclic peptide endowed with sub-nanomolar binding affinity toward the αvβ6 receptor and remarkable selectivity against other integrins. Computational studies were performed to disclose the molecular bases underlying the high binding affinity and receptor subtype selectivity of this peptide.

Complementary, Selective PET Imaging of Integrin Subtypes α5β1 and αvβ3 Using 68Ga-Aquibeprin and 68Ga-Avebetrin.

Unlabelled: Despite in vivo mapping of integrin αvβ3 expression being thoroughly investigated in recent years, its clinical value is still not well defined. For imaging of angiogenesis, the integrin subtype α5β1 appears to be a promising target, for which purpose we designed the PET radiopharmaceutical (68)Ga-aquibeprin.

Methods: (68)Ga-aquibeprin was obtained by click-chemistry (CuAAC) trimerization of a α5β1 integrin-binding pseudopeptide on the triazacyclononane-triphosphinate (TRAP) chelator, followed by automated (68)Ga labeling.

Phosphaturic Mesenchymal Tumor: 2 New Oral Cases and Review of 53 Cases in the Head and Neck.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that secretes fibroblast growth factor-23 (FGF-23) and causes oncogenic osteomalacia. It occurs in adults with equal gender distribution and the most common location is the lower extremities, followed by the head and neck. Besides osteomalacia, the clinical presentation includes bone pain and multiple bone fractures.

Is there anything we can modify among factors associated with morbidity following elective laparoscopic sigmoidectomy for diverticulitis?

Background: Laparoscopic sigmoidectomy for diverticulitis is widely accepted, using either endolinear staplers or traditional linear staplers under direct vision through the extraction site to transect the rectum. The aim of this study was to assess modifiable factors affecting perioperative morbidity after elective laparoscopic sigmoidectomy for diverticulitis.

Methods: Potential associations between perioperative morbidity and demographic, disease-related, and treatment-related factors were assessed on all consecutive patients included in a prospectively collected database undergoing elective laparoscopic sigmoidectomy for diverticulitis between 1992 and 2013.

Bioactive compounds immobilized on Ti and TiNbHf: AFM-based investigations of biofunctionalization efficiency and cell adhesion.

Implant materials require optimal biointegration, including strong and stable cell-material interactions from the early stages of implantation. Ti-based alloys with low elastic modulus are attracting a lot of interest for avoiding stress shielding, but their osseointegration potential is still very low. In this study, we report on how cell adhesion is influenced by linear RGD, cyclic RGD, and recombinant fibronectin fragment III8-10 coated on titanium versus a novel low-modulus TiNbHf alloy.

In vivo biokinetic and metabolic characterization of the ⁶⁸Ga-labelled α5β1-selective peptidomimetic FR366.

Purpose: Integrins are transmembrane receptors responsible for cell-cell adhesion and cell-extracellular matrix binding and play an important role in angiogenesis and tumour metastasis. For this reason, integrins are increasingly used as targets for molecular imaging. Up to now interest has mostly been focused on the integrin subtype αvβ3.

Caveolin-1-negative head and neck squamous cell carcinoma primary tumors display increased epithelial to mesenchymal transition and prometastatic properties.

Distant metastases arise in 20-30% of patients with squamous cell carcinoma of the head and neck (HNSCC) in the 2 years following treatment. Therapeutic options are limited and the outcome of the patients is poor. The identification of predictive biomarkers of patient at risk for distant metastasis and therapies are urgently needed.

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma.

Integrin α5β1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5β1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer therapy.

cis-Peptide Bonds: A Key for Intestinal Permeability of Peptides? .

Recent structural studies on libraries of cyclic hexapeptides led to the identification of common backbone conformations that may be instrumental to the oral availability of peptides. Furthermore, the observation of differential Caco-2 permeabilities of enantiomeric pairs of some of these peptides strongly supports the concept of conformational specificity driven uptake and also suggests a pivotal role of carrier-mediated pathways for peptide transport, especially for scaffolds of polar nature. This work presents investigations on the Caco-2 and PAMPA permeability profiles of 13 selected N-methylated cyclic pentaalanine peptides derived from the basic cyclo(-D-Ala-Ala4 -) template.

The diagnostic challenges of separating chronic ulcerative stomatitis from oral lichen planus.

Objective: To attempt to establish criteria to differentiate between chronic ulcerative stomatitis (CUS) and oral lichen planus (OLP) with hematoxylin and eosin (H&E) staining alone.

Study Design: Ten confirmed cases of CUS were reviewed from the Stomatology Clinic at the Texas A&M University Baylor College of Dentistry.

Results: The original diagnosis on H&E evaluation was OLP, chronic mucositis, or mucositis with lichenoid features, but subsequent direct immunofluorescence (DIF) revealed a positive speckled intranuclear deposition of immunoglobulin G (IgG) in the basal and parabasal layers of the epithelium, confirming a diagnosis of CUS.

Human Hippocampal Dynamics during Response Conflict.

Besides its relevance for declarative memory functions, hippocampal activation has been observed during disambiguation of uncertainty and conflict. Uncertainty and conflict may arise on various levels. On the perceptual level, the hippocampus has been associated with signaling of contextual deviance and disambiguation of similar items (i.

Oral melanocytic nevi: a clinicopathologic study of 100 cases.

Objective: The purpose of this study was to evaluate the clinical and histopathologic features of oral melanocytic nevi (OMN).

Study Design: One hundred cases of OMN were retrieved from the files of two oral pathology services, and the data were analyzed with regard to histologic type and clinical features.

Results: Intramucosal nevus was the most common type (61%), followed by common blue nevus (23%), compound nevus (7%), and junctional nevus (3%).

Minimal synthetic cells to study integrin-mediated adhesion.

To shed light on cell-adhesion-related molecular pathways, synthetic cells offer the unique advantage of a well-controlled model system with reduced molecular complexity. Herein, we show that liposomes with the reconstituted platelet integrin αIIb β3 as the adhesion-mediating transmembrane protein are a functional minimal cell model for studying cellular adhesion mechanisms in a defined environment. The interaction of these synthetic cells with various extracellular matrix proteins was analyzed using a quartz crystal microbalance with dissipation monitoring.

Systematic Backbone Conformational Constraints on a Cyclic Melanotropin Ligand Leads to Highly Selective Ligands for Multiple Melanocortin Receptors.

Human melanocortin receptors (hMCRs) have been challenging targets to develop ligands that are explicitly selective for each of their subtypes. To modulate the conformational preferences of the melanocortin ligands and improve the biofunctional agonist/antagonist activities and selectivities, we have applied a backbone N-methylation approach on Ac-Nle-c[Asp-His-D-Nal(2')-Arg-Trp-Lys]-NH2 (Ac-Nle(4)-c[Asp(5),D-Nal(2')(7),Lys(10)]-NH2), a nonselective cyclic peptide antagonist at hMC3R and hMC4R and an agonist at hMC1R and hMC5R. Systematic N-methylated derivatives of Ac-Nle(4)-c[Asp(5),D-Nal(2')(7),Lys(10)]-NH2, with all possible backbone N-methylation combinations, have been synthesized and examined for their binding and functional activities toward melanocortin receptor subtypes 1, 3, 4, and 5 (hMCRs).

Relationship among knowledge acquisition, motivation to change, and self-efficacy in CME participants.

Introduction: The relationship among an individual's sense of self-efficacy, motivation to change, barriers to change, and the implementation of improvement programs has been reported. This research reports the relationship among self-efficacy, motivation to change, and the acquisition of knowledge in a continuing medical education (CME) activity.

Methods: The measure of individual sense of self-efficacy was a 4-item scale.

Renal Function Recovery and HIV Viral Suppression Following Tenofovir Discontinuation for Renal Impairment.

Background: Tenofovir associated nephrotoxicity (TDFN) is well recognized. This study describes the trend of renal function recovery and virologic consequences after cessation of tenofovir (TDF) for suspected TDFN.

Methods: This was a retrospective chart review of 241 patients who underwent HLA-B*5701 allele testing between January 2007-December 2010.

Segregation versus colocalization: orthogonally functionalized binary micropatterned substrates regulate the molecular distribution in focal adhesions.

Orthogonally functionalized binary micropatterned substrates are produced using a novel protocol. The use of adequate peptido-mimetics enables an unprecedented segregation of purified αvβ3 and α5β1 integrins in adjacent microislands and evidences the preference of U2OS cells to colocalize such receptors. Moreover, this tendency can be altered by varying the geometry and composition of the micropatterns.

Evaluation of the COBAS(®) AmpliPrep/COBAS(®) TaqMan(®) HCV Test, v2.0 and comparison to assays used in routine clinical practice in an international multicenter clinical trial: The ExPECT study.

Background: The COBAS(®) AmpliPrep(®)/COBAS(®) TaqMan(®) HCV Test, v2.0 (CAP/CTM2) is used for HCV RNA viral load monitoring.

Objectives: The performance of the CAP/CTM2 was compared to other widely used tests, including a manual version of the assay (the COBAS(®) TaqMan(®) HCV Test, v2.

Enantiomeric cyclic peptides with different Caco-2 permeability suggest carrier-mediated transport.

Recently, oral absorption of cyclic hexapeptides was improved by N-methylation of their backbone amides. However, the number and position of N-methylations or of solvent exposed NHs did not correlate to intestinal permeability, measured in a Caco-2 model. In this study, we investigate enantiomeric pairs of three polar and two lipophilic peptides to demonstrate the participation of carrier-mediated transporters.

Hsp90 regulates the dynamics of its cochaperone Sti1 and the transfer of Hsp70 between modules.

The cochaperone Sti1/Hop physically links Hsp70 and Hsp90. The protein exhibits one binding site for Hsp90 (TPR2A) and two binding sites for Hsp70 (TPR1 and TPR2B). How these sites are used remained enigmatic.

Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging.

Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy.

Interface Immobilization Chemistry of RGD-based Peptides Regulates Integrin Mediated Cell Adhesion.

The interaction of specific surface receptors of the integrin family with different extracellular matrix-based ligands is of utmost importance for the cellular adhesion process. A ligand consists of an integrin-binding group, here cyclic RGDfX, a spacer molecule that lifts the integrin-binding group from the surface and a surface anchoring group. (-RGDfX-) peptides are bound to gold nanoparticle structured surfaces via polyproline, polyethylene glycol or aminohexanoic acid containing spacers of different lengths.